Ganglion cell-inner plexiform layer thinning and colorectal cancer risk: phenotypic and genetic evidence for shared pathways

BACKGROUND: Colorectal cancer (CRC), the third most prevalent malignancy globally, urgently requires novel screening approaches. Although retinal structural abnormalities have emerged as biomarkers for systemic disorders, their association with CRC remains largely unexplored. METHODS: A total of 38 370 participants from UK Biobank, who were free of CRC at baseline, were included in the current study. Retinal structure measurements were obtained using optical coherence tomography (OCT), including ganglion cell-inner plexiform layer (GCIPL). Cox proportional hazards regression models were used to examine longitudinal associations between OCT-quantified retinal layer thicknesses and incident CRC. To elucidate potential biological mechanisms, we performed comprehensive phenotypic and genetic analyses. The phenotypic analyses incorporated multivariable linear regression and mediation analysis to quantify CRC-related factor contributions. Genetic analyses included linkage disequilibrium score regression, MiXeR analysis, conditional/conjunctional false discovery rate (condFDR/conjFDR), and Mendelian randomization (MR) to explore the shared genetic architecture. RESULTS: Over a median follow-up period of 11.27 years, 461 (1.2%) participants developed CRC. In the fully adjusted model, each standard deviation increase in baseline GCIPL thickness was associated with a 10% decrease in incident CRC risk (hazard ratio = 0.90, 95% confidence interval: 0.81-0.99, P = 0.025). CRC-related factors including physical activity, non-communicable chronic diseases, and body mass index were associated with GCIPL thickness variations and BMI mediated 1.62% of the GCIPL-CRC association. Genetic analyses for the GCIPL-CRC association demonstrated significant common genetic variants. MiXeR identified 40 shared causal variants. The condFDR/conjFDR discovered 196 SNPs linked to 32 protein-coding genes. Gene Ontology analysis highlighted enrichment in chromatin remodeling pathways. MR analysis showed no evidence of causal associations. CONCLUSIONS: GCIPL thinning is independently associated with increased CRC risk. Mechanistic analyses suggest this association is driven by shared risk factors and common genetic variants, rather than direct causation. These findings suggest retinal imaging may serve as an indicator of systemic processes influencing CRC.